MHC multimer

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MHC multimers are oligomeric forms of MHC molecules, designed to identify and isolate T-cells with high affinity to specific antigens amid a large group of unrelated T-cells. [1] Multimers generally range in size from dimers to octamers; however, some companies use even higher quantities of MHC per multimer. Multimers may be used to display class 1 MHC, class 2 MHC, or nonclassical molecules (e.g. CD1d) from species such as monkeys, mice, and humans.

Contents

Background

Since T-cell receptors have a low affinity for their MHC counterparts, it was historically problematic to label T cells effectively using single MHC-T-cell interactions. [2] However, in 1996 it was proposed by John Altman to use a complex of multiple MHC molecules to form a more stable bond between corresponding T-cells. [3]

Production

The most commonly used MHC multimers are tetramers. [3] These are typically produced by biotinylating soluble MHC monomers, which are typically produced recombinantly in eukaryotic or bacterial cells. These monomers then bind to a backbone, such as streptavidin or avidin, creating a tetravalent structure. These backbones are conjugated with fluorochromes to subsequently isolate bound T-cells via flow cytometry. [4]

Potential clinical applications

MHC multimers allow for a previously unattainable level of specificity in antigen-specific T-cell detection and isolation. This ability gives rise to several clinical applications. MHC multimers allow for ex vivo selection and proliferation of T-cells specific to viral or tumor-related antigens, which can then be reintroduced to augment the immune system. MHC multimers can also be used to eliminate graft-originating T-cells on transplant organs, ex vivo. MHC multimers may also be used to eliminate harmful or unwanted T-cells in vivo, such as those that target self cells and lead to autoimmune disease. [4] [5] [6] Cancer immunotherapy and vaccine development can also be largely influenced by this technology. [7]

Sub-types

MHC tetramer

MHC tetramers consist of four MHC molecules, a tetramerization agent and a fluorescently labeled protein (usually streptavidin). Streptavidins have also been generated with 6 or 12 binding sites for MHC. [8] MHC tetramers are used to identify and label specific T-cells by epitope specific binding, allowing the antigen specific immune response to be analyzed in both animal model and in human. [9] MHC tetramers were originally developed using MHC class I molecules for the recognition of cytotoxic T cells, [10] [11] but over the last decade they have allowed for the recognition of CD4 T cells by a wide variety of antigens. Tetramer assays are used for single-cell phenotyping and cell counting, and offer an important advantage over other methods, such as ELISPOT and single-cell PCR because they enable the recovery and further study of sorted cells. As a flow-cytometry-based application, tetramers are also easy to use and have a short assay time, similar to Antibody-based flow cytometry studies. [4]

MHC tetramers are used in studies of pathogen immunity and vaccine development, in evaluation of antitumor responses, in allergy monitoring and desensitization studies, and in autoimmunity. [4] [12] They provide an ideal means to characterize the T cells that respond to a vaccine, and they have been used to test T cell responses in many vaccine systems, including influenza, [13] yellow fever, [14] tuberculosis, [15] HIV/SIV [16] and a large number of cancer vaccine trials, [17] including melanoma and chronic myeloid leukemia. [18] Class II tetramers have been used for analysis of a variety of human CD4 T cell responses to pathogens, including influenza A, Borrelia, Epstein–Barr virus, CMV, Mycobacterium tuberculosis, human T-lymphotropic virus 1, hepatitis C, anthrax, severe acute respiratory syndrome virus, human papillomavirus, and HIV. [4] Tetramer variants have been developed that, either radiolabelled or coupled to a toxin such as saporin, can be injected into live mice to modulate or even deplete specific T cell populations. [19] [20] Peptide–MHC tetramers have also been used therapeutically. [21] For instance, cytomegalovirus-specific T cells have been enriched to high levels of purity using magnetic bead-based enrichment for use as a therapy for stem cell transplant patients. [12]

MHC pentamer

Pentamers consist of five MHC-peptide headgroups, arranged in a planar configuration so that, unlike MHC tetramers, all of the headgroups can contact the CD8+ T cell. The headgroups are connected via flexible linkers to a coiled-coil multimerization domain, which in turn is connected to five fluorescent or biotin tags. Pentamers are available with APC, R-PE, or biotin labelling, and also unlabelled with separate tags for long-term storage. Pentamers offer enhanced brightness and avidity of staining compared with other multimer reagents.

MHC pentamers have been used in the detection of antigen-specific CD8+ T cells in flow cytometry, [12] and are cited in over 750 peer reviewed publications , including several in the journals Nature [22] and Science. [23] [24] MHC pentamers can also be used in tissue staining, [25] and in magnetic isolation of antigen-specific T cells. [26]

While pentamers are licensed for research use only, in 2009 a special dispensation was granted for a team to use them for isolating EBV-specific T cells for mother-daughter transfer, for lifesaving treatment of EBV-associated lymphoma in the daughter. [27]

Pentamers are available for antigens from the following disease areas: adenovirus, HCV, malaria, SIV, autoimmune disease, HIV, transplantation antigens, trypanosoma, cancer, HPV, tuberculosis, chlamydia, HTLV, vaccinia, CMV, influenza, VSV, EBV, LCMV, RSV, West Nile virus, HBV, Listeria , Sendai virus, yellow fever. Custom specificity pentamers may also be commissioned.

Pentamers are currently used in research by academia, industry and clinicians, and research using pentamers has appeared in the international media on several occasions.

MHC Dextramer®

A form of MHC multimer developed and trademarked by the Danish biotechnology company, Immudex in 2002. Dextramer reagents are fluorescently labeled with FITC, PE or APC, and contain MHC molecules attached to a dextran backbone, which are used to detect antigen-specific T-cells in fluid cells and solid tissue samples using flow cytometry. These T-cells contain T-cell receptors (TCR) that recognize a specific MHC-peptide complex displayed on the surface of antigen presenting cells allowing for detection, isolation, and quantification of these specific T-cell populations due to an improved signal-to-noise ratio not present in prior generations of multimers. [3] [12] [28]

Dextramer® reagents have been developed with a larger number of MHC-peptides for various human, mouse, and rhesus macaque genes involved in diseases including but not limited to: cancer, HIV, Epstein–Barr virus (EBV), cytomegalovirus (CMV), LCMV, human papillomavirus (HPV), BK polyomavirus, HTLV, hepatitis, mycobacterium, and graft-versus-host disease.

Dextramer technology is currently used in academic and clinical research due to their increased specificity and binding affinity, which allows for increased avidity for specific T-cells and enhances staining intensity. This advantage is a result of the increased ability of Dextramers to bind multiple times to a single T-cell, improving the stability of this interaction as compared with other multimer technologies such as pentamers and tetramers. Further applications include the ability to isolate antigen specific T-cell populations as well as in situ detection using immunohistochemistry (IHC) for various disease states (e.g. solid tumors). These reagents are therefore important for future drug and vaccine development. [1] [12] [28] [29] [30]

Immudex developed a CMV Dextramer® assay for exploratory detection and quantification of CD8+ T-cells in blood samples, covering a broad range of epitopes to assist with screening and monitoring CMV progression in future clinical settings. [31] MHC Dextramer® reagents are available with MHC class I and MHC class II molecules. [32]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">DNA vaccine</span> Vaccine containing DNA

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized are also epitopes.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

<span class="mw-page-title-main">MHC class I</span> Protein of the immune system

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits, and heterotetramers are complexes of different subunits. A tetramer can be assembled as dimer of dimers with two homodimer subunits, or two heterodimer subunits.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

A tetramer assay is a procedure that uses tetrameric proteins to detect and quantify T cells that are specific for a given antigen within a blood sample. The tetramers used in the assay are made up of four major histocompatibility complex (MHC) molecules, which are found on the surface of most cells in the body. MHC molecules present peptides to T-cells as a way to communicate the presence of viruses, bacteria, cancerous mutations, or other antigens in a cell. If a T-cell's receptor matches the peptide being presented by an MHC molecule, an immune response is triggered. Thus, MHC tetramers that are bioengineered to present a specific peptide can be used to find T-cells with receptors that match that peptide. The tetramers are labeled with a fluorophore, allowing tetramer-bound T-cells to be analyzed with flow cytometry. Quantification and sorting of T-cells by flow cytometry enables researchers to investigate immune response to viral infection and vaccine administration as well as functionality of antigen-specific T-cells. Generally, if a person's immune system has encountered a pathogen, the individual will possess T cells with specificity toward some peptide on that pathogen. Hence, if a tetramer stain specific for a pathogenic peptide results in a positive signal, this may indicate that the person's immune system has encountered and built a response to that pathogen.

<span class="mw-page-title-main">Antonio Lanzavecchia</span> Italian and Swiss immunologist

Antonio Lanzavecchia is an Italian and Swiss immunologist. As a fellow of Collegio Borromeo he obtained a degree with honors in Medicine in 1976 from the University of Pavia where he specialized in Pediatrics and Infectious Diseases. He is Head Human Immunology Program, Istituto Nazionale di Genetica Molecolare-INGM, Milan and SVP Senior research Fellow, Humabs/Vir Biotechnology, Bellinzona and San Francisco (USA). Since 2017, he is also Professor at the Faculty of Biomedical Sciences of the Università della Svizzera italiana (USI).

<span class="mw-page-title-main">CD74</span> Mammalian protein found in Homo sapiens

HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74, is a protein that in humans is encoded by the CD74 gene. The invariant chain is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses. The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).

<span class="mw-page-title-main">MLANA</span> Protein-coding gene in the species Homo sapiens

Protein melan-A also known as melanoma antigen recognized by T cells 1 or MART-1 is a protein that in humans is encoded by the MLANA or "MALENA" gene. A fragment of the protein, usually consisting of the nine amino acids 27 to 35, is bound by MHC class I complexes which present it to T cells of the immune system. These complexes can be found on the surface of melanoma cells. Decameric peptides (26-35) are being investigated as cancer vaccines.

<span class="mw-page-title-main">Trogocytosis</span>

Trogocytosis is when a cell nibbles another cell. It is a process whereby lymphocytes conjugated to antigen-presenting cells extract surface molecules from these cells and express them on their own surface. The molecular reorganization occurring at the interface between the lymphocyte and the antigen-presenting cell during conjugation is also called "immunological synapse".

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

Immunomics is the study of immune system regulation and response to pathogens using genome-wide approaches. With the rise of genomic and proteomic technologies, scientists have been able to visualize biological networks and infer interrelationships between genes and/or proteins; recently, these technologies have been used to help better understand how the immune system functions and how it is regulated. Two thirds of the genome is active in one or more immune cell types and less than 1% of genes are uniquely expressed in a given type of cell. Therefore, it is critical that the expression patterns of these immune cell types be deciphered in the context of a network, and not as an individual, so that their roles be correctly characterized and related to one another. Defects of the immune system such as autoimmune diseases, immunodeficiency, and malignancies can benefit from genomic insights on pathological processes. For example, analyzing the systematic variation of gene expression can relate these patterns with specific diseases and gene networks important for immune functions.

Immudex is a Danish Reagents and Diagnostics company established in 2009. The company is operating from offices located in Copenhagen, Denmark, and in Fairfax, Virginia. Immudex specializes in the production of MHC Dextramers. MHC Dextramers are chemical reagents that are designed to detect antigen-specific T cells.

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced. That is, despite multiple allelic variations of MHC molecules and multiple peptides presented on antigen presenting cells, the immune response is skewed to only specific combinations of the two. Immunodominance is evident for both antibody-mediated immunity and cell-mediated immunity. Epitopes that are not targeted or targeted to a lower degree during an immune response are known as subdominant epitopes. The impact of immunodominance is immunodomination, where immunodominant epitopes will curtail immune responses against non-dominant epitopes. Antigen-presenting cells such as dendritic cells, can have up to six different types of MHC molecules for antigen presentation. There is a potential for generation of hundreds to thousands of different peptides from the proteins of pathogens. Yet, the effector cell population that is reactive against the pathogen is dominated by cells that recognize only a certain class of MHC bound to only certain pathogen-derived peptides presented by that MHC class. Antigens from a particular pathogen can be of variable immunogenicity, with the antigen that stimulates the strongest response being the immunodominant one. The different levels of immunogenicity amongst antigens forms what is known as dominance hierarchy.

References

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